REGULATION OF LEUKOCYTE-ENDOTHELIUM INTERACTION AND LEUKOCYTE TRANSENDOTHELIAL MIGRATION BY INTERCELLULAR-ADHESION MOLECULE 1-FIBRINOGEN RECOGNITION

Although primarily recognized for its role in hemostasis, fibrinogen is also required for competent inflammatory reactions in vivo, It is now shown that fibrinogen promotes adhesion to and migration across an endothelial monolayer of terminally differentiated myelomonocytic cells, This process does not require chemotactic/haptotactic gradients or cytokine stimulation of the endothelium and is specific for the association of fibrinogen with intercellular adhesion molecule 1 (ICAM-1) on endothelium, Among other adhesive plasma proteins, fibronectin fails to increase the binding of leukocytes to endothelium, or transendothelial migration, whereas vitronectin promotes the binding but not the migration, The fibrinogen-mediated leukocyte adhesion and transendothelial migration could be inhibited by a peptide from the fibrinogen gamma-chain sequence N(117)NQKIVNLKEKVAQLEA(133), which blocks the binding of fibrinogen to ICAM-1. This interaction could also be inhibited by new anti-ICAM-1 monoclonal antibodies that did not affect the ICAM-1-CD11a/CD18 recognition, thus suggesting that the fibrinogen binding site on ICAM-1 may be structurally distinct from regions previously implicated in leukocyte-endothelium interaction, Therefore, binding of fibrinogen to vascular cell receptors is sufficient to initiate (i) increased leukocyte adhesion to endothelium and (ii) leukocyte transendothelial migration, These two processes are the earliest events of immune inflammatory responses and may also contribute to atherosclerosis.